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oai:repisalud.isciii.es:20.500.12105/65262024-11-29T14:31:00Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud author Mortuza, Gulnahar B author Hermida, Dario author Pedersen, Anna-Kathrine author Segura-Bayona, Sandra author López-Méndez, Blanca author Redondo P, Pilar author Rüther, Patrick author Pozdnyakova, Irina author Garrote, Ana M author Muñoz, Ines Gabriela author Villamor-Payà, Marina author Jauset, Cristina author Olsen, Jesper V author Stracker, Travis H author Montoya, Guillermo funder Novo Nordisk Foundation funder Danish Cancer Foundation funder Ministerio de Economía y Competitividad (España) funder Fundación La Caixa 2018-10-25T09:02:52Z 2018-10-25T09:02:52Z 2018-06-28 Nat Commun. 2018; 9(1): 2535. 10.1038/s41467-018-04941-y 2041-1723 2041-1723 Nature communications 29955062 http://hdl.handle.net/20.500.12105/6526 Tousled-like kinases (TLKs) are required for genome stability and normal development in numerous organisms and have been implicated in breast cancer and intellectual disability. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear. Here we describe the crystal structure of the TLK2 kinase domain. We show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity. We show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies. Together our results provide insights into the structure and molecular regulation of the TLKs. eng DNA-DAMAGE CHECKPOINT PROTEIN-KINASE S-PHASE GENOMIC INSTABILITY BREAST-CANCER CELL-CYCLE REPLICATION ASF1 PHOSPHORYLATION IDENTIFICATION Molecular basis of Tousled-Like Kinase 2 activation journal article TElDRU5DSUEgREUgRElTVFJJQlVDScOTTiBOTyBFWENMVVNJVkEKCkFjZXB0YW5kbyBlc3RhIGxpY2VuY2lhLCBVc3RlZCAoZWwgYXV0b3IvZXMgbyBlbCBwcm9waWV0YXJpby9zIGRlIGxvcyBkZXJlY2hvcyBkZSAKYXV0b3IpIGNvbmNlZGUgYSBSRVBJU0FMVUQgZWwgZGVyZWNobyBubyBleGNsdXNpdm8gZGUgcmVwcm9kdWNpciwgY29udmVydGlyLCB5L28gCmRpc3RyaWJ1aXIgc3UgZG9jdW1lbnRvIChpbmNsdXllbmRvIHN1IHJlc3VtZW4pIGEgbml2ZWwgbXVuZGlhbCBlbiBmb3JtYXRvIGRpZ2l0YWwsIAppbmNsdXllbmRvLCBhdWRpbyB5IHbDrWRlbywgYSB0cmF2w6lzIGRlIHN1IHJlcG9zaXRvcmlvIGluc3RpdHVjaW9uYWwuCgpVc3RlZCBhY2VwdGEgcXVlIFJFUElTQUxVRCBwdWVkZSwgc2luIGFsdGVyYXIgc3UgY29udGVuaWRvLCBjb252ZXJ0aXIgc3UgZG9jdW1lbnRvIAphIGN1YWxxdWllciBvdHJvIGZvcm1hdG8gZGlnaXRhbCBkZSBkYXRvcywgYXVkaW8geSB2aWRlbywgY29uIGVsIHByb3DDs3NpdG8gZGUgcXVlIApwdWVkYSBzZXIgYWxvamFkbyBlbiBlbCByZXBvc2l0b3Jpby4gCgpVc3RlZCBlc3TDoSBkZSBhY3VlcmRvIGNvbiBxdWUgUkVQSVNBTFVEIHB1ZWRhIGNvbnNlcnZhciBtw6FzIGRlIHVuYSBjb3BpYSBkZSBlc3RlIApkb2N1bWVudG8gcGFyYSBhc2VndXJhciBzdSBzZWd1cmlkYWQsIHByZXNlcnZhY2nDs24geSBhY2Nlc28uCgpVc3RlZCBkZWNsYXJhIHF1ZSBlbCBkb2N1bWVudG8gZXMgdW4gdHJhYmFqbyBvcmlnaW5hbCwgeSBxdWUgdGllbmUgZWwgZGVyZWNobyBkZSAKb3RvcmdhciBsb3MgZGVyZWNob3MgY29udGVuaWRvcyBlbiBlc3RhIGxpY2VuY2lhLiBUYW1iacOpbiBkZWNsYXJhIHF1ZSBzdSBwZXRpY2nDs24gCm5vIGluZnJpbmdlIGxvcyBkZXJlY2hvcyBkZSBhdXRvciBkZSBuYWRpZS4gCgpTaSBlbCBkb2N1bWVudG8gY29udGllbmUgbWF0ZXJpYWxlcyBwYXJhIGxvcyBxdWUgbm8gc2UgdGllbmVuIGxvcyBkZXJlY2hvcyBkZSBhdXRvciwgClVzdGVkIGRlY2xhcmEgcXVlIGhhIG9idGVuaWRvIGVsIHBlcm1pc28gc2luIHJlc3RyaWNjacOzbiBkZWwgcHJvcGlldGFyaW8gZGUgbG9zIApkZXJlY2hvcyB5IHF1ZSBlbiBkaWNobyBtYXRlcmlhbCwgZXN0w6EgY2xhcmFtZW50ZSBpZGVudGlmaWNhZGEgeSByZWNvbm9jaWRhIHN1IAphdXRvcsOtYSBkZW50cm8gZWwgdGV4dG8gbyBkZWwgY29udGVuaWRvIGRlIGRpY2hvIGRvY3VtZW50by4gCgpTaSBlbCBlbnbDrW8gc2UgYmFzYSBlbiB1biB0cmFiYWpvIHF1ZSBoYSBzaWRvIHBhdHJvY2luYWRvIG8gYXBveWFkbyBwb3IgdW5hIGFnZW5jaWEgCnUgb3JnYW5pemFjacOzbiBkaXN0aW50YSBhIFJFUElTQUxVRCwgdXN0ZWQgYWNlcHRhIHF1ZSBoYSBjdW1wbGlkbyBjb24gZWwgZGVyZWNobyBkZSAKcmV2aXNpw7NuIHkgb3RyYXMgb2JsaWdhY2lvbmVzIHJlcXVlcmlkYXMgcG9yIGNvbnRyYXRvIG8gYWN1ZXJkby4gCgpSRVBJU0FMVUQgaWRlbnRpZmljYXLDoSBjbGFyYW1lbnRlIHN1KHMpIG5vbWJyZShzKSBjb21vIGF1dG9yKHMpIG8gcHJvcGlldGFyaW8ocykgCmRlbCBkb2N1bWVudG8sIHkgbm8gaGFyw6EgbmluZ3VuYSBhbHRlcmFjacOzbiwgZXhjZXB0byBzZWfDum4gbG8gcGVybWl0aWRvIHBvciBlc3RhIApsaWNlbmNpYS4gCg== URL https://repisalud.isciii.es/bitstreams/78aef95f-c64e-4a62-8767-bc93abd4f129/download File MD5 4a4796a33ed26e53d31257323aa00d35 2779433 application/pdf MolecularbasisofTousledLike_2018.PDF URL https://repisalud.isciii.es/bitstreams/061ed2f2-c9e5-48c3-ab85-7b90edf4b063/download File MD5 f7a7566cb9bb0f26d70c08c593f68bcb 87360997 application/pdf MolecularbasisofousledLikeKinase2activation._MOESM1_ESM(1)_2018.pdf URL https://repisalud.isciii.es/bitstreams/61937ea0-ccc7-4e41-b58d-0c0d17077cee/download File MD5 a381c9e2e109609eb25a7b7952908168 283067 application/pdf Molecularbasisoftousled-LikeKinase 2activation_MOESM2_ESM_2018.pdf URL https://repisalud.isciii.es/bitstreams/69063ac6-0415-4afa-9ff9-8e897e7d7721/download File MD5 195e1240c1a7b32a8661bdfc61e34a31 77182 application/pdf MolecularbasisofTousled-LikeKinase2 activation._MOESM3_ESM_2018.pdf URL https://repisalud.isciii.es/bitstreams/3a7b9d47-e6d0-4fd1-8e35-8a0afe5b21af/download File MD5 66a698656ad2ead8a0d6d610d56f1c7b 239831 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Molecularbasisoftousted_MOESM4_ESM_2018.xlsx URL https://repisalud.isciii.es/bitstreams/26971ce9-4003-4440-b157-deae55de9abb/download File MD5 fa45400d7461b0f56b819e5d04a2c72f 98578 text/plain MolecularbasisofTousledLike_2018.PDF.txt URL https://repisalud.isciii.es/bitstreams/3663fe24-88f5-44a9-90f5-d2e72f0cdbf7/download File MD5 2caf09cc8271e2415e58b1409e19db3e 48122 text/plain MolecularbasisofousledLikeKinase2activation._MOESM1_ESM(1)_2018.pdf.txt URL https://repisalud.isciii.es/bitstreams/b7dd2f33-508a-452d-b3c4-e845962aa6a6/download File MD5 705301315e0f6e09653bcfa9edd4b281 43941 text/plain Molecularbasisoftousled-LikeKinase 2activation_MOESM2_ESM_2018.pdf.txt URL https://repisalud.isciii.es/bitstreams/8ba71fa5-06c9-4c7b-96fd-c566a608bcae/download File MD5 3fd9caf18de923a9e11c460aafa21f20 1455 text/plain MolecularbasisofTousled-LikeKinase2 activation._MOESM3_ESM_2018.pdf.txt URL https://repisalud.isciii.es/bitstreams/46a5046d-7a58-4531-89af-f42095a8f412/download File MD5 6c63b0ccc620faf3d916577b16a1c41c 100000 text/plain Molecularbasisoftousted_MOESM4_ESM_2018.xlsx.txt